Opioid antagonists, such as naltrexone and naloxone, are used in relatively high (i.e., milligram) doses for a variety of treatments including but not limited to eating disorders, narcotic dependence, and alcoholism. Treatment may involve administering the drug by oral tablet (e.g., REVIA™) or by parenteral injection, at doses in the range of 50 mg by tablet daily or 380 mg per month by intramuscular depot. U.S. Pat. No. 6,565,449 to Stinchcomb et al., describes the delivery of a prodrug of the opioid antagonist naltrexone and a transdermal delivery apparatus for same.
Dopamine is a neurotransmitter, or chemical messenger, that sends information to parts of the brain that control movement, coordination, cognitive functions, and emotions. There are five distinct dopamine receptors, which differ in terms of their pharmacological profiles and cellular distribution. The D2 receptor and the D3 receptor share many signaling pathways, are the main targets for most drugs used to treat extrapyramidal movement disorders as well as antipsychotic drugs, and are heavily expressed in the regions of the brain responsible for motor functions and emotional functions, respectively. In addition, some studies have shown that abnormal function of the D2 and D3 receptors are closely related to schizophrenia. Due to the critical role of these two dopamine receptors in terms of neurological function, many drugs have been used that target these receptors to affect dopamine related activity. However, the use of dopamine D2 and/or D3 receptor full and partial agonists in the treatment of neurological and psychiatric disorders is limited by desensitization of the dopamine D2 and/or D3 receptor induced by repeated use of such drugs, which undesirably can lead to a loss or diminution of therapeutic effects. The diminution in therapeutic effects may lead to the need for higher doses with the risk of untoward side effects. An unwanted loss of effect at the end of the dosing interval, as described by terms “wearing off” or “on-off”, is thought to be a consequence of change in the constitutive activity of D2 and D3 receptors as discussed below.
Drugs which produce higher levels of extracellular dopamine also are used to treat neurological and psychiatric disorders, and can analogously produce dopamine D2 and/or D3 receptor desensitization. These agents increase extracellular dopamine levels by augmenting dopamine synthesis, by blocking reuptake of extracellular dopamine into dopamine neurons, by releasing dopamine from dopamine neurons, or by decreasing metabolic degradation of dopamine. Typically, drugs that increase extracellular dopamine levels have therapeutic effects which decrease with repeated administration or require higher doses of drugs, which may lead to side effects or a loss of the therapeutic properties of the drugs earlier in the dosing interval. This diminution or loss of therapeutic effects is likely related to desensitization of dopamine D2 and/or D3 receptors induced by chronic elevation of extracellular dopamine levels.
Parkinson's Disease occurs when a group of cells in the substansia nigra that produce dopamine begin to malfunction and die. As discussed above, dopamine is a neurotransmitter, or chemical messenger, that sends information to the parts of the brain that control movement and coordination. When a patient has Parkinson's Disease, his dopamine-producing cells begin to die, and therefore, the amount of dopamine produced in the brain decreases. Signals from the brain that tell the body how and when to move are therefore delivered more slowly, leaving a person incapable of initiating and controlling movements in a normal way. The four primary symptoms of Parkinson's Disease are tremor, or trembling in hands, arms, legs, jaw, and face; rigidity, or stiffness of the limbs and trunk, bradykinesia, or slowness of movement; and postural instability, or impaired balance and coordination. Other symptoms may include depression and other emotional changes; difficulty in swallowing, chewing, and speaking; urinary problems of constipation; skin problems; and sleep disruptions.
At present, there is no cure for Parkinson's Disease, but a variety of medications provide dramatic relief from the symptoms. Patients are often given levodopa (L-DOPA, 3,4-dihydroxy-L-phenylalanine) formulations including, but not limited to, combinations of levodopa with carbidopa (SINE-MET™). Carbidopa delays the conversion of levodopa into dopamine until it reaches the brain. Nerve cells can use levodopa to make dopamine and replenish the brain's dwindling supply. Although levodopa helps many Parkinson's patients, not all symptoms respond equally to the drug. For example, bradykinesia and rigidity typically respond to this drug; however, tremor may only be marginally reduced and problems with balance and other symptoms may not be alleviated at all. Another typical therapy for Parkinson's Disease is the use of anticholinergic medications such as benztropine mesylate (COGENTIN™) and biperiden hydrochloride (AKINETON™) which block nerve impulses to help improve muscle control and which decrease levels of acetylcholine in order to achieve a closer balance with dopamine levels. Anticholinergic medications may only help control tremor and rigidity and not other associated symptoms. Other drugs referred to as dopamimetics including, but not limited to, bromocriptine, pergolide, pramipexole, and ropinirole, mimic the role of dopamine in the brain, causing the neurons to react as they would to dopamine. However, these dopamimetic drugs are not without undesirable side effects. It would be desirable to develop new or improved therapies for the treatment of Parkinson's Disease.
RLS is a neurological disorder characterized by unpleasant sensations in the legs and a strong urge to move when at rest in an effort to relieve these feelings. RLS sensations are often described by people as burning, creeping, tugging, or like insects crawling inside the legs. Often called paresthesias (abnormal sensations) or dysesthesias (unpleasant abnormal sensations), the sensations range in severity from uncomfortable to irritating to painful. Several prescription medications, most of which were developed to treat other diseases, are available to reduce the restlessness in the legs. These include medications for Parkinson's Disease, opioids, muscle relaxants, sleep medications, and medications for epilepsy.
Medications for Parkinson's Disease are the most common treatment for RLS. These medications include pramipexole (MIRAPEX™), pergolide (PERMAX™), ropinirole (REQUIP™), and a combination of carbidopa and levodopa (SINEMET™). However, as mentioned above, these medications have undesirable side effects including abrupt daytime sedation, on-off or wearing off effects, and tolerance requiring higher doses. Higher doses of the dopamimetics repinirole and pramipexole have been associated with compulsive gambling, inappropriate hypersexuality, and drowsiness which may occur suddenly during the day, potentially leading to adverse consequences, such as automobile accidents.
A common problem with the currently available dopamimetic treatments for RLS is tolerance. That is, a medication and dose that has previously been effective for relief of RLS symptoms becomes ineffective, or the symptoms return earlier. Tolerance leads to the use of higher doses of the medications, which increase the probability of unwanted side effects.
Major depressive disorder is a condition characterized by a pervasive low mood and loss of interest or pleasure in usual activities. The majority of currently used antidepressants target a limited number of neurotransmitter binding sites or transporters, particularly the serotonin transporter and serotonin receptors including 5HT2A and 5HT1A receptors, the norepinephrine transporter, the dopamine transporter and dopamine D2 and D3 receptors. Pharmacotherapy based on these agents fails to produce full remission in at least 30% of patients suffering major depressive episodes. Anhedonia, a global loss of pleasurable feelings, is a core symptom of depression and is believed to be mediated by decreased or abnormal dopamine neurotransmission in the limbic system, particularly the ventral striatum. A number of studies have implicated dysfunction of limbic dopaminergic neurotransmission in the etiology of anhedonia. There remains a significant need for new and improved antidepressant treatment for patients suffering from depression, especially refractory depression.
It also would be desirable to provide new or improved pharmaceutical formulations and methods for the treatment of symptoms associated with Parkinson's Disease, Restless Leg Syndrome, attention deficit disorder, schizophrenia, psychostimulant drug abuse, and other conditions for which augmentation of dopamine D2 and/or D3 neurotransmission is therapeutically beneficial that overcome the problems associated with the currently available treatments. In particular, it would be desirable to provide therapies that minimize or prevent desensitization to dopamine augmentation.
It would be desirable treat Parkinson's Disease, RLS, depression, particularly refractory depression, attention deficit disorder, schizophrenia, and psychostimulant drug abuse by modulating the dopamine system, increasing dopamine levels without causing tolerance or on-off effects. In particular, it would be desirable to prevent tolerance to the effects of drugs which directly stimulate dopamine D2 and D3 receptors or which elevate extracellular dopamine levels by modulating dopamine D2 and/or D3 receptor signaling.